The present invention relates to novel and useful derivatives of the antiviral agent Ara-A. In particular the invention relates to novel prodrug forms which are low melting, lipid soluble and permeable through topical membranes such as skin, ophthalmic membranes and the like.
For the purpose of this specification, the term "prodrug" denotes a derivative of a known and proven prior art antiviral compound which derivative when administered to warm blooded animals cleaves in such a manner as to release the proven drug form at its target site of activity. The enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug from (Ara-A) is released and permits the same to attain a higher bioavailability leve than that which could be obtained if the proven drug form per se was administered. The cleaved moiety is metabolized to nontoxic metabolic products.
Ara-A is an antimetabolite with a very high therapeutic index that is effective when used systemically against herpes zoster infections in immuno-suppressed patients and patients with herpes simplex encephalitis. It is also effective topically against herpes simplex keratitis of the eye when used as the monophosphate. Despite its efficacy, its low aqueous solubility, (0.4 mg/ml) at 25.degree. and poor lipophilicity precludes its use as a topical agent for treating genital, oral and other cutaneous herpes infections. It is believed that between 20 and 45 percent of the United States population are affected by recurrent herpes simplex labialis. A recent double-blind radomized study with 233 patients with topical Ara-A monophosphate proved its ineffectiveness because of the failure of the drug to penetrate the skin and reach the infected cells to inhibit viral replication [New England J. Med. 300, 1180 (1979)]. In vitro drug diffusion studies in human vaginal mucosa and foreskin showed minimal penetration of the drug across the skin. But in the hairless mouse model of herpes simplex skin infection, increasing the skin penetration of the drug by iontophoresis enhanced efficacy. It is also known the derivatization of the 5'-hydroxyl group of Ara-A inhibits deamination of the adenine nucleus by adenosine deaminase to give 9-.beta.-D-arabinofuranosylhypoxanthine the major metabolite which has little antiviral activity.
Thus there exists a clear and present need for novel latentiated forms of Ara-A, which derivatives would be conspicuously devoid of those disadvantages and drawbacks that to date have characterized the prior art compounds.
The object of the present invention is to provide suitable prodrugs of Ara-A with greater lipophilicity and hence increased potential for biomembrane transport and in addition, resistance to adenosine deaminase, the enzyme responsible for metabolic deactivation.
Derivatization of Ara-A has been accomplished before, but this consists mostly of esterification of the hydroxyl group(s) of the arabinose residue and irreversible acylation or alkylation of N-1 and/or N.sup.6 of the adenine moiety (T. H. Haskell, Ana. N.Y. Acad. Sci., 284, 81 (1977) and U.S. Pat. Nos. 3,651,045; 4,048,432; 4,055,718 and 4,055,717).
Though the reaction of nucleosides with formaldehyde has been studied extensively during the last three decades, the addition product of formaldehyde to aminopurines and especially to the adenine moiety of the nucleosides in aqueous solutions has never be isolated and characterized (D. M. Brown "Reactions of Polynucleotides and Nucleic Acids" in Basic Principles of Nucleic Acid Chemistry, Ed., P. O. P. Tso, Vol. II, p. 24, Academic Press, 1974).